Macrophage migration inhibitory factor (MIF) accounts for one of the first cytokine activities to have been described, and it has emerged recently to be an important regulator of innate and adaptive immunity. MIF is an upstream activator of monocytes/macrophages, and it is centrally involved in the pathogenesis of septic shock, arthritis, and other inflammatory conditions. The protein is encoded by a unique but highly conserved gene, and X-ray crystallography studies have shown MIF to define a new protein fold and structural superfamily. Although recent work has begun to illuminate the signal transduction pathways activated by MIF, the nature of its membrane receptor has not been known. Using expression cloning and functional analysis, we report herein that CD74, a Type II transmembrane protein, is a high-affinity binding protein for MIF. MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal–regulated kinase–1/2 MAP kinase cascade, cell proliferation, and PGE2 production. A recombinant, soluble form of CD74 binds MIF with a dissociation constant of ∼9 × 10−9 K d, as defined by surface plasmon resonance (BIAcore analysis), and soluble CD74 inhibits MIF-mediated extracellular signal–regulated kinase activation in defined cell systems. These data provide a molecular basis for MIF's interaction with target cells and identify it as a natural ligand for CD74, which has been implicated previously in signaling and accessory functions for immune cell activation.

https://rupress.org/jem/article-pdf/197/11/1467/1144323/jem197111467.pdf

MIF signal transduction initiated by binding to CD74.

MHC class II-associated invariant chain contains a sorting signal for endosomal compartments.

Class II molecules of the major histocompatibility complex (MHC) bind peptides derived from protein antigens delivered into endocytic compartments and present these peptides to CD4+ T cells. The precursors to functional MHC class II molecules loaded with peptides are complexes of the invariant chain associated with class II alpha beta heterodimers. Targeting of newly synthesized MHC class II molecules to endosomes is mediated by the invariant chain, but the intracellular transport route is not known. This study demonstrates that in a human B-cell line a large population of MHC class II-invariant chain complexes reaches endosomes by rapid internalization from the cell surface. Quantitation of cell surface MHC class II-invariant chain complexes and of their surface half-life revealed that 3000 complexes internalized per minute into endosomes. This highly efficient endocytosis was mediated by the cytoplasmic tail of the invariant chain. After internalization, the invariant chain dissociated from the MHC class II-invariant chain complexes. This pathway may represent an important mechanism for loading class II molecules with immunogenic peptides from several endocytic compartments.

https://www.pnas.org/content/pnas/90/18/8581.full.pdf

Cell surface HLA-DR-invariant chain complexes are targeted to endosomes by rapid internalization

In most human and mouse antigen-presenting cells, the majority of intracellular major histocompatibility complex (MHC) class II molecules resides in late endocytic MHC class II compartments (MIICs), thought to function in antigen processing and peptide loading. However, in mouse A20 B cells, early endocytic class II-containing vesicles (CIIVs) have been reported to contain most of the intracellular MHC class II molecules and have also been implicated in formation of MHC class II-peptide complexes. To address this discrepancy, we have studied in great detail the endocytic pathways of both a human (6H5.DM) and a mouse (A20.Ab) B cell line. Using quantitative immunoelectron microscopy on cryosections of cells that had been pulse-chased with transferrin-HRP or BSA-gold as endocytic tracers, we have identified up to six endocytic subcompartments including an early MIIC type enriched in invariant chain, suggesting that it serves as an important entrance to the endocytic pathway for newly synthesized MHC class II/invariant chain complexes. In addition, early MIICs represented the earliest endocytic compartment containing MHC class II- peptide complexes, as shown by using an antibody against an abundant endogenous class II-peptide complex. The early MIIC exhibited several though not all of the characteristics reported for the CIIV and was situated just downstream of early endosomes. We have not encountered any special class II-containing endocytic structures besides those normally present in nonantigen-presenting cells. Our results therefore suggest that B cells use conventional endocytic compartments rather than having developed a unique compartment to accomplish MHC class II presentation.

/pdf/major-histocompatibility-complex-class-ii-compartments-in-5082bki96h.pdf

Major Histocompatibility Complex Class II Compartments in Human and Mouse B Lymphoblasts Represent Conventional Endocytic Compartments

We have examined trafficking of major histocompatibility complex (MHC) class II molecules in human B cells exposed to concanamycin B, a highly specific inhibitor of the vacuolar H(+)-ATPases required for acidification of the vacuolar system and for early to late endosomal transport. Neutralization of vacuolar compartments prevents breakdown of the invariant chain (Ii) and blocks conversion of MHC class II molecules to peptide-loaded, SDS-stable alpha beta dimers. Ii remains associated with alpha beta and this complex accumulates internally, as ascertained biochemically and by morphological methods. In concanamycin B-treated cells, a slow increase (> 20-fold) in surface expression of Ii, mostly complexed with alpha beta, is detected. This surface-disposed fraction of alpha beta Ii is nevertheless a minor population that reaches the cell surface directly, or is routed via early endosomes as intermediary stations. In inhibitor-treated cells, the bulk of newly synthesized alpha beta Ii is no longer accessible to fluid phase endocytic markers. It is concluded that the majority of alpha beta Ii is targeted directly from the trans-Golgi network to the compartment for peptide loading, bypassing the cell surface and early endosomes en route to the endocytic pathway.

/pdf/how-mhc-class-ii-molecules-reach-the-endocytic-pathway-4dyy2nus46.pdf

How MHC class II molecules reach the endocytic pathway.

http://www.jbc.org/content/265/10/5787.full.pdf

Human major histocompatibility complex class II invariant chain is expressed on the cell surface.

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Human major histocompatibility complex class II invariant chain is expressed on the cell surface.